Project Summary Despite the essential role of alveolar type 1 (AT1) cells in gas exchange, the AT1 cell has not received much attention within the context of lung development, maintenance, and disease. We found that AT1 specific deletion of the transcription factor NK homeobox2.1 (NKX2.1) during development results in loss of three defining features of AT1 cells, as well as adoption of an alternative cell fate. This led to our hypothesis that NKX2.1 is a key transcriptional regulator of development and maintenance of AT1 cells. We will investigate the epigenetic mechanisms of NKX2.1 dependent transcriptional control in developing AT1 cells (aim 1) and determine the role of NKX2.1 in mature AT1 cells as well as its contribution to lung injury (aim 2). Successful completion of this study will elucidate the first transcription factors known to regulate AT1 development and maintenance, paving the way for future investigation of AT1 cells in lung development and disease. .